There is a global urgency to develop a protective AIDS vaccine. Neutralizing antibodies (Nabs) can provide effective prophylaxis against HIV-1 infections. Although eliciting Nabs that are broadly cross-reactive has long been a major scientific challenge, we have recently generated a mini-protein containing the membrane-proximal external region (MPER) of gp41 that can elicit Nabs with significant breadth. The primary objective of this proposal is to develop novel vaccine delivery platforms that can enhance B cell immune responses. The underlying hypothesis behind this proposal is that a polymeric antigen containing many copies of the same target epitope in a repetitive, well-defined lattice (multivalent) can elicit a superior B cell immune response than a monomeric antigen (monovalent) because of its potential to (1) induce both T cell-independent (Tl) and -dependent (TD) B cell immunity; (2) enhance B cell activation and maturation; and (3) activate a greater diversity of B cell subsets. To test this hypothesis, we will develop novel vaccine delivery platforms based on nanostructures designed to present multivalent forms of immunogens and costimulatory molecules to B cells and to facilitate targeted delivery of antigens to dendritic cells and macrophages. Successful completion of the proposed studies would represent a major advancement towards developing a protective AIDS vaccine. The proposed research Program consists of two Projects and two Cores: The role of Project 1 is to develop vaccine delivery platforms. The role of Project 2 is to evaluate B cell immune responses against gp41- MPER in great detail. The Administrative Core is responsible for providing the organizational management and maintaining infrastructure to support the fiscal monitoring. The Protein Production Core is responsible for producing and providing high quality antigens and costimulatory molecules to Projects 1 and 2. This is a highly collaborative program project of seven key investigators from five institutions.